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Gout management: urate lowering therapy

Gout management: urate lowering therapy. 12 recommendations were produced on the basis of literature evidence and expert opinion Ability to improve clinical practice Conceived in 2004-5 The future research agenda included points to be examined further

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Gout management: urate lowering therapy

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  1. Gout management: urate lowering therapy

  2. 12 recommendations were produced on the basis of literature evidence and expert opinion • Ability to improve clinical practice • Conceived in 2004-5 • The future research agenda included points to be examined further • Update to be performed to include advances in knowledge and new drugs Zhang W, et al. Ann Rheum Dis 2006;65:1312-1324

  3. EULAR recommendations 2006 for the management of gout 7 Urate lowering therapy is indicated in patients with recurrent acute attacks, arthropathy, tophi, or radiographic changes of gout. The therapeutic goal of urate lowering therapy is to promote crystals dissolution and prevent crystal formation; this is achieved by maintaining the serum uric acid below the saturation point for monosodium urate (≤360 μmol/l). Allopurinol is an appropriate long-term urate lowering drug; it should be started at a low dose (for example 100mg daily), and increased by 100mg every 2-4 weeks if required; the dose should be adjusted in patients with renal impairment; if allopurinol toxicity occurs, options include other xanthine oxidase inhibitors, a uricosuric agent, or allopurinol desensitisation (the latter only in cases of mild rash). Uricosuric agents such as probenecid and sulphinpyrazone can be used as an alternative to allopurinol in patients with normal renal function but are relatively contra-indicated in patients with urolithiasis; benzbromarone can be used in patients with mild to moderate renal insufficiency on a named patient basis but carries a small risk of hepatotoxicity. Prophylaxis against acute attacks during the first months of urate lowering therapy can be achieved by colchicines (0.5 – 1mg daily) and/or an NSAID (with gastro-protection if indicated). When gout associates with diuretic therapy, stop the diuretic if possible; for hypertension and hypelipidemia consider use of losartan and fenofibrate, respectively (both have modest uricosuric effects). 8 9 10 11 12 Zhang W, et al. Ann Rheum Dis 2006;65:1312-1324.

  4. 7 7 EULAR recommendations 2006 for the management of gout Uric acid lowering therapy is indicated in gout patients with recurrent acute attacks, arthropathy, tophi or radiographic changes of gout. Future research agenda The indications for initiating urate lowering treatment (for example, recurrent acute attacks, tophi, polyarticular acute attacks, radiographic joint damage) need further evaluation. Zhang W, et al. Ann Rheum Dis 2006;65:1312-1324.

  5. Indications for urate-lowering therapy • Based on risk/benefit ratio assessment • Sparse research data to guide the decision as to when to start urate-lowering drug treatment • Uniform agreement on this therapy in patients with severe established gout - as indicated, for example, by tophi, gouty arthropathy, radiographic changes of gout, multiple joint involvement, or associated uric acid nephrolithiasis • Less agreement on this therapy in patients with less severe gout - for example, following clinical presentation with the first acute attack • No agreement for patients with asymptomatic hyperuricaemia Zhang W, et al. Ann Rheum Dis 2006;65:1301-11. Richette P, et al. Lancet 2010;375:318-328. Terkeltaub R. Nature Rev Rheumatol 2010:6:30-38.

  6. Factors encouraging the use of ULT after a single attack of gout • Presence of comorbidities • Severe or complicated gout • Impaired renal function • Advanced age • Particular benefit from prevention • Risk associated with the treatment of acute attacks • Patient’s wishes Zhang W, et al. Ann Rheum Dis 2006;65:1301-1311. Richette P, et al. Lancet 2010;375:318-328. Terkeltaub R. Nature Rev Rheumatol 2010:6:30-38.

  7. Urate-lowering agents currently available in most European countries Zhang W, et al. Ann Rheum Dis 2006;65:1301-1311. Richette P, et al. Lancet 2010;375:318-328. Perez-Ruiz F. Rheumatology 2009;48:ii9-ii14.

  8. Objectives of urate lowering therapy • The goal of treatment is to cure • the patient by lowering the sUA • enough to dissolve urate crystals • and prevent further crystal • formation and thus: • prevent acute gout attacks • resolve tophi and prevent further tophus formation • prevent joint damage Dissolution of urate crystal deposition from a tophus By kind permission of L. Punzi, Rheumatology Unit, University of Padua Zhang W, et al. Ann Rheum Dis 2006;65:1312-1324.

  9. 8 3 EULAR recommendations 2006 for the management of gout The therapeutic goal of urate-lowering therapy is to promote crystal dissolution and prevent crystal formation. This is achieved by maintaining the serum uric acid below the saturation point for monosodium urate (≤360 mmol/L or ≤6 mg/dl) Future research agenda Further studies are required to determine the target SUA for urate lowering treatment that ensures crystal dissolution and eventual cure Zhang W, et al. Ann Rheum Dis 2006;65:1312-1324.

  10. Treat to target • EULAR guidelines advocate maintaining sUA <6 mg/dl1 (<360 μmol/l) • “The therapeutic goal of urate lowering therapy is to promote crystal dissolution and prevent crystal formation. This is achieved by maintaining the serum uric acid below the saturation point for monosodium urate (6 mg/dl or 360 μmmol/l)” • sUA is presumed to be an indicator of levels in the joint • BSR (UK) guidelines advocate maintaining sUA 5 mg/dl2 (<300 μmol/l) 1. Zhang W, et al. Ann Rheum Dis 2006;65:1312-1324. 2. Jordan KM, et al. Rheumatol (Oxford) 2007;46(8):1372-1374 .

  11. 9 Allopurinol EULAR recommendations 2006 for the management of gout Allopurinol is an appropriate long-term urate-lowering therapy. It should be started at a low dose (e.g. 100 mg daily) and increased by 100 mg every 2-4 weeks if required. The dose must be adjusted in patients with renal impairment. If allopurinol toxicity occurs, options include other xanthine oxidase inhibitors, a uricosuric agent or allopurinol desensitisation (the latter only in cases of mild rash) Zhang W, et al. Ann Rheum Dis 2006;65:1312-1324.

  12. Oxypurinol Terkeltaub R. Nature Rev Rheumatol 2010:6:30-38.

  13. 9 Steven-Johnson syndrome Erythema multiforme EULAR recommendations 2006 for the management of gout Allopurinol is an appropriate long-term urate-lowering therapy. It should be started at a low dose (e.g. 100 mg daily) and increased by 100 mg every 2-4 weeks if required. The dose must be adjusted in patients with renal impairment. If allopurinol toxicity occurs, options include other xanthine oxidase inhibitors, a uricosuric agent or allopurinol desensitisation (the latter only in cases of mild rash). By kind permission of L. Punzi,Rheumatology Unit, University of Padua Zhang W, et al. Ann Rheum Dis 2006;65:1312-1324.

  14. 2012 American College of Rheumatology Guidelines for Management of Gout Significance & innovations (I) “The starting dosage of allopurinol should be no greater than 100 mg/day and less than that in moderate to severe chronic kidney disease (CKD), followed by gradual upward titration of the maintenance dose, which can exceed 300 mg daily even in patients with CKD” Khanna D, et al. Arthritis Care & Research 2012;64,(10):1431-46.

  15. Allopurinol safety • Hypersensitivity reactions (2-4%) • Skin (mild to severe; fatal) • Fever, hepatitis, nephritis, hematologic • AHS (allopurinol hypersensitivity syndrome) • Mechanism: type IV ? • Non-immunologic toxicity • renal, liver • animal toxicity: renal, liver, cardiac • Unclear whether hypersensitivity related to allopurinol, oxypurinol or other metabolite Zhang W, et al. Ann Rheum Dis 2006;65:1301-1311. Richette P, et al. Lancet 2010;375:318-328. Perez-Ruiz F. Rheumatology 2009;48:ii9-ii14.

  16. 4 EULAR recommendations 2006 for the management of gout Future research agenda for gout management Direct comparison (efficacy, side effects, cost utility) between allopurinol and alternative urate lowering treatments are needed. Zhang W, et al. Ann Rheum Dis 2006;65:1312-1324

  17. 2012 American College of Rheumatology Guidelines for Management of Gout Significance & innovations (II) “Xanthine oxidase inhibitor (XOI) therapywith either allopurinol or febuxostat is recommendedasthe first-line pharmacologic urate-loweringtherapy (ULT) approach in gout.” (Evidence Level A) Khanna D, et al. Arthritis Care & Research 2012; 64,(10):1431-46.

  18. Febuxostat: pharmacodynamics • Non purine compound • Selective Inhibitor of Xanthine Oxidase (SIXO) • Inhibits both (oxidized and reduced) forms of XO • Intense, dose-dependent linear reduction of serum urate CH3 O H3C N NC CH3 S Febuxostat CO2H Khosravan Clin Pharmacokinet 2006;45:821-841.

  19. Febuxostat: pharmacokinetics • Bioavailability • > 80% PO, Tmax: 1.0-1.5 hour, t1/2: 5-8 hours • Not influenced by food or antiacids • Metabolism • In the liver, excretion mainly as inactive metabolites • By the kidneys and through the bile • No clinically relevant interactions with • Thiazides • Warfarin • NSAIDs • Colchicine • No clinically relevant PK changes in • Mild-to-moderate renal function impairment • Mild-to-moderate liver function impairment SmPC febuxostat.

  20. Febuxostat: clinical trial overview Study 004 153 patients Phase II studies FOCUS Open-label extension study 116 patients 5 years APEX 1,072 patients 6 months EXCEL Open-label extension study 1,086 patients 3 years FACT 760 patients 1 year Phase III studies CONFIRMS 2,269 patients 6 months Becker MA. Arthritis Rheum 2005;52:916-923. Becker MA. N Engl J Med 2005;353:2450-2461. Schumacher HR. Arthritis Rheum2008;59:1540-1548. Schumacher HR. Rheumatol 2009;48:188-194. Becker MA. J Rheumatol 2009;36:1273-1282. Becker MA. Arthrits Res Ther 2010;12:R63.

  21. Febuxostat - clinical efficacy in phase II RCT Percentage of patients reaching sUA targets at day 28 <6 mg/dl (360 mcmol/l) <5 mg/dl (300 mcmol/l) <4 mg/dl (240 mcmol/l) 100 94% 88% 80 76% 70 60 56% 56% 49% 50 % of patients 40 30 21% 19% 20 10 0% 0 Placebo 40 mg/day 80 mg/day 120 mg/day Becker MA, et al. Arthritis Rheum 2005;52:916-923.

  22. Febuxostat - phase III studies: patients’ demographics • Mostly male (94%) • Average of ≥10 years with history ofgout • 63%: overweight to obese (BMI>30 Kg/m2) • 50%: history of arterial hypertension • 38%: history of hyperlipidaemia • 23%: tophus at baseline • Mean sUA at baseline: 9.97 mg/dl (600 μmol/l) Schumacher HR. Arthritis Rheum2008;59:1540-1548. Becker MA. N Engl J Med 2005;353:2450-2461. Becker MA. Arthrits Res Ther 2010;12:R63.

  23. Cod. MCI296-1405 The FACT Study Becker MA, et al. N Engl J Med 2005;353:2450-61. Beara-Lasic L, et al. Int J Nephrol Renovasc Dis 2010;3:1-10.

  24. Cod. MCI296-1405 The APEX Study * 100 mg in patients with serum creatinine 1.5-2.0 mg/dl Becker MA, et al. N Engl J Med 2005;353:2450-61. Beara-Lasic L, et al. Int J Nephrol Renovasc Dis 2010;3:1-10.

  25. Febuxostat - clinical efficacy in phase III studies Percentage of patients reaching serum urate < 6 mg/dl (360 µmol/l) ITT analysis, at last visit . Schumacher HR. Arthritis Rheum2008;59:1540-1548. Becker MA. N Engl J Med 2005;353:2450-2461. Becker MA. Arthrits Res Ther 2010;12:R63. *40 mg/day not registered in EU **145/757 patients in the CONFIRMS on 200 mg/day **10/263 patients in the APEX trial on 100 mg/day

  26. EXCEL study: switch data • Patients switching due to sUA >6.0 mg/dl (>360 μmol/l) • Febuxostat 80 mg to febuxostat 120 mg: 22% (141/649) • Febuxostat 120 mg to allopurinol 300 mg:8% (22/292) • Allopurinol to febuxostat80 mg: 57% (82/145) Patients who reached 6.0 mg/dl (<360 μmol/l) after switching 80 70 64% 60 50 % of patients 40 30 17% 20 10 0 Febuxostat to allopurinol Allopurinolto febuxostat (n=4/24) (n=50/78) Becker MA, et al. J Rheumatol 2009;36:1273-1282.

  27. Febuxostat is effective in patients with renal impairment APEX study (6 months): proportion of renal impaired (1.5–2 serum creatinine [>133–177 mol/l]) subjects with last 3 sUA levels6.0 mg/dl (<360 μmol/l) * 50 * 46% 44% *p0.05 all febuxostat doses vs allopurinol and placebo 40 30 % of patients 20 10 0% 0% 0 Placebo Febuxostat 80 mg Febuxostat 120 mg Allopurinol 100 mg (n=5) (n=9) (n=11) (n=10) ITT population: subjects with serum urate level 8.0 mg/dl on day -2 Schumacher HR, et al. Arthritis Rheum 2008;59:1540-1548.

  28. Greater reduction in tophussize with lower sUA FACT study (1 year): % change from baseline in primary tophus size at week 52 Post-baseline sUA (mg/dl) 7 6-7 5-6 4-5 <4 0% 0 -20% -20 -45% -49% -40% -40 -50% % change in tophus size (n=15) (n=22) (n=17) -60 -60% -85% -84% -80% -80 (n=13) (n=18) -100 Data for ALL patients, drawn from Becker MA, et al. N Engl J Med 2005;353:2450-2461.

  29. Febuxostat - patients requiring treatment for a flare FOCUS study (5 years): percentage of subjects requiring treatment for flares while receiving maintenance treatment ‘N’ represents the total number of subjects on a final stable dose of febuxostat for the duration designated and ‘n’ is the total number of subjects that reported at least one gout flare that required treatment in the given time interval. Schumacher HR, et al. Rheumatology 2009;48:188-194.

  30. Cod. MCI2961409 Characteristics of patients in the post-hoc analysis of renal function during febuxostat treatment Variable All Subjects N = 551 Male, n (%) 528 (95.8) Race, n (%) - Caucasian 437 (79.3) Age, y, mean ± SD 51.3 ± 11.59 BMI - ≥ 30 kg/m2, n (%) 357 (64.8) - Mean, kg/m2 ± SD 32.7 ± 5.84 - Alcohol use, n (%) 361 (65.5) Years with gout, mean ± SD 11.0 ± 9.04 Tophi present, n (%) 100 (18.1) SUA level, mg/dL, mean ± SD 9.8 ± 1.26 Medical history, n (%) - Cardiovascular disease 59 (10.7) - Diabetes 32 (5.8) - Hypertension 236 (42.8) Abbreviations: BMI = body mass index SD = standard deviation SUA = serum uric acid Whelton A, et al. Postgrad Med 2013;125:106-14.

  31. Cod. MCI2961409 Change in renal function over time in relation to change in serum uric acid levels Whelton A, et al. Postgrad Med 2013;125:106-14.

  32. Cod. MCI2961409 Febuxostat preserved renal function Whelton A, et al. Postgrad Med 2013;125:106-14.

  33. Cod. MCI2961409 Possible mechanisms of renal function preservation with febuxostat • Inhibition of the deleterious effects of up-regulated xanthine oxidase in the vasculature • Lowering blood pressure in the renal vasculature • Progressive mobilisation of monosodium urate microdeposits from renal tissues Whelton A, et al. Postgrad Med 2013;125:106-14.

  34. Cod. MCI296-1405 The FACT Study Becker MA, et al. N Engl J Med 2005;353:2450-61. Beara-Lasic L, et al. Int J Nephrol Renovasc Dis 2010;3:1-10.

  35. Cod. MCI296-1405 The APEX Study * 100 mg in patients with serum creatinine 1.5-2.0 mg/dl Becker MA, et al. N Engl J Med 2005;353:2450-61. Beara-Lasic L, et al. Int J Nephrol Renovasc Dis 2010;3:1-10.

  36. Febuxostat - fewer patients require treatment for gout flare over time EXCEL study (3 years): patients requiring treatment for gout flare All patients receiving allopurinol without reaching the sUA target level were switched to febuxostat. Becker MA, et al. J Rheumatol 2009;36:1273-1282.

  37. Febuxostat - overall safety in phase III studies Percentage of patients with serious adverse events (SAE) . Schumacher HR. Arthritis Rheum2008;59:1540-1548. Becker MA. N Engl J Med 2005;353:2450-2461. Becker MA. Arthrits Res Ther 2010;12:R63. *145/757 patients in the CONFIRMS on 200 mg/day *10/263 patients in the APEX trial on 100 mg/day

  38. Main clinical differences between febuxostat and allopurinol SmPC: allopruinol, febuxostat. Schumacher HR. Arthritis Rheum2008;59:1540-1548. Becker MA. N Engl J Med 2005;353:2450-2461.

  39. Cod. MCI296-1405 Advantages of febuxostat from the patient’s prespective • Dosing is always once a day • Dosing simplified by the fact that only two dose levels are available • Typically achieves target serum urate levels more rapidly than allopurinol • More effective than usual doses of allopurinol in lowering serum uric acid levels • No dose adjustments necessary for mild to moderate renal impairment • No dose adjustments necessary on the basis of age or gender • The recommended dose in patients with mild hepatic impairment is 80 mg • Appears to be a better agent for reducing tophi • An alternative to allopurinol for patients with allopurinol hypersensitivity Beara-Lasic L, et al. Int J Nephrol Renovasc Dis 2010;3:1-10.

  40. Clinical applicability of febuxostat • Intolerance to other ULT • Severe urate deposition • Target urate < 4-5 mg/dl • Target urate 240-300 μmol/l • High baseline serum urate • Renal function impairment • Moderate (uricosurics) • Difficult adjustment of doses (allopurinol) Perez-Ruiz F, Future Rheumatology 2008;3(5):421-427.

  41. Febuxostat - clinical management (I) • No dose adjustment needed • Elderly • Mild to moderate renal function impairment • Mild to moderate liver function impairment • No dose adjustment needed while on • Colchicine, indomethacin, naproxen • Warfarin • Hydrochlorothiazide • CYP 2D6 substrates SmPC febuxostat.

  42. Febuxostat - clinical management (II) • Doses registered: 80 and 120 mg PO qd • Initial dose: 80 mg/day • Maximum dose: 120 mg/day • Efficacy • Evaluable already after 2-4 week’s exposure to 80 mg qd • Increase to 120 mg if target (<6 mg/dl) sUA not achieved • Safety • Prophylaxis to avoid flares >6 months • Liver function tests • Moderate ethanol intake SmPC febuxostat.

  43. Febuxostat - special precautions • Febuxostat is not recommended in: • Patients with ischaemic heart disease or congestive heart failure • Patients being treated with mercaptopurine or azathioprine • Patients with severe renal function impairment (no experience) • Patients with severe liver impairment (no experience) • Caution is required when febuxostat is used in: • Patients being treated with theophylline • Patients with thyroid disorders SmPC febuxostat..

  44. Febuxostat - summary • Febuxostat is a non-purine inhibitor of xanthine oxidase (XO) • selective inhibition of both isoforms of XO • The urate-lowering effect of febuxostat 80 mg/day is greater than that of allopurinol 300 mg/day • Target serum urate on ULT not achieved in a significant proportion of patients on allopurinol 300 mg/day • Febuxostat is overall well tolerated and comparable in tolerability to allopurinol • Febuxostat may become an interesting choice for the treatment of hyperuricaemia of gout • Treatment with febuxostat in patients with ischaemic heart disease or congestive heart failure is not recommended Perez-Ruiz F. Future Rheumatol 2006;3:421-7, Becker MA. N Engl J Med 2005;353:2450-61, Schumacher HR. Arthritis Rheum 2008;59:1540-8, Becker MA. Arthrits Res Ther 2010;12:R63. SmPC febuxostat.

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